The polysystic ovary syndrome (PCOS) is a poorly understood disorder that affects approximately 6-10 percent of women of reproductive age. PCOS is characterized by hyperandrogenism and chronic anovulation, and is the leading cause of female infertility in the United States. Women with PCOS are also at high risk for developing type 2 diabetes, presumably due to the insulin resistance that accompanies the syndrome. Our long-term goal is to elucidate the relationship between insulin resistance and PCOS, especially as it relates to hyperandrogenism. Some actions of insulin may be effected by putative inositolphosphoglycan (IPG) mediators of insulin action and a deficiency in a specific D-chiro-inositol-containing IPG may contribute to insulin resistance in individuals with impaired glucose tolerance or type 2 diabetes. Our studies indicate that D-chiro-inositol (DCI) administration improves glucose intolerance while reducing circulating insulin in women with PCOS, and is also associated with decreases in serum androgens and improved ovulatory function. In addition, our in vitro studies in human thecal cell cultures suggest that the IPG signaling system plays a role in transducing insulin's stimulation of ovarian androgen biosynthesis. These studies have led us to focus our short- term goals on an assessment of the role of the IPG signaling system in PCOS, and pursue a unifying hypothesis to explain the above experimental observations. Our hypothesis is that women with PCOS are DCI deficient, perhaps related to an intracellular defect in the conversion of myo-inositol (MYO) to DCI. This results in a decrease in a DCI-containing IPG mediator (DCI-IPG) and an increase in a MYO-containing IPG mediator (MYO-IPG) bound to the outer leaflet of the cell membrane. We further propose that the resulting deficient insulin-mediated release of DCI-IPG contributes to insulin resistance in PCOS, whereas the simultaneous hyperinsulinemia mediated increased release of MYO-IPG at the level of the ovary acts to stimulate ovarian androgen biosynthesis. If our proposed studies confirm a role for IPG's in insulin resistance and hyperandrogenism of PCOS, they will substantially enhance our understanding of the disorder's pathogenesis and are likely to provide insights into novel treatment strategies directed specifically at the IPG system and normalization of its function.